*2.2.1 Lesions in small vessel wall*

Microvascular changes in the retinal capillaries are due to chronic hyperglycemia by different mechanisms, such as:

### *2.2.1.1 Aldose-reductase and intracellular polyol pathway*

Aldose reductase is an enzyme that converts glucose to sorbitol, which induces osmotic stress by intracellular accumulation. In animal models, this phenomenon leads to microaneurysmal dilatations of the vascular wall, basal membrane thickening and loss of the pericytes [47]. However, experimental studies of treatment with aldose reductase inhibitors have not obtained satisfactory clinical results.

#### *2.2.1.2 Advanced glycosylated end products (AGEs)*

Chronic hyperglycemia leads to non-enzymatic glycation or glycoxidation of proteins, resulting in accumulation of AGEs. This process affects both intra- and extracellular proteins, resulting in functional impairment. Deposits of AGEs in the extracellular matrix and subendothelial space lead to permanent alterations of intercellular junctions, monocyte migration and activation of nuclear factor (NF) *κ*B along with activation of pro-inflammatory pathways [48, 49]. In experimental models, increased AGEs accumulation is associated with loss of pericytes and microaneurysm formation in retinal capillaries [50].

#### *2.2.1.3 Oxidative stress and ROS*

Hyperglycemia induces mitochondrial dysfunction and endoplasmic reticulum stress, with increased production of free radicals and reactive oxygen species (ROS) accumulation [49]. These degrade lipids, proteins and ribonucleic acid (RNA) chains.

**253**

potentials [56–60].

*Microvascular Complications of Diabetes Mellitus: Focus on Diabetic Retinopathy (DR)…*

Furthermore, experimental studies have proved a "hyperglycemic memory": in subjects with long periods of poor glycemic control, reversal of hyperglycemia fails to normalize increased oxidative activity in the retina [51]. Treatment with antioxidants and vitamin E alleviates endothelial dysfunction, but does not prevent the onset and progression of DR and other microvascular complications. Isolated experimental blockade of each of these pathways does not stop retinal microvascular damage, suggesting that the effects of hyperglycemia are manifested at the cellular and extracellular levels. Recently, experimental and clinical studies have demonstrated that inflammation biomarkers and pathways play a significant role in the aggravation of lesions and the evolution towards retinal neovascularization. A large array of cytokines and chemokines were found in increased concentrations in patients with DM, both in ocular samples and in serum: interleukin (Il)1beta, Il 2, 4, 6, 8, TNFalfa and (monocyte chemoattractant protein) MCP-1 [38, 42, 52–54]. Recent works have revealed that the TXNIP/NLRP3 Inflammasome activation pathways may contribute to pathologic neovascularization encountered in advanced stages of PDR [50, 54, 55].

Hyperglycemia induces decreased synthesis and increased consumption of NO by multiple pathways: activation of protein kinase C (PKC) in endothelial cells, oxidation of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) via aldose reductase pathway, and non-enzymatic production of superoxide by AGEs. NO plays key roles in microcirculation, by regulation of arteriolar tone, platelet stabilization and preventing leukocyte adherence at the vascular wall. Decreased local levels of NO promotes vasoconstriction, microvascular occlusions

General changes in blood favor small vessel obstructions with secondary retinal

• activation of peripheral leukocytes, increased adherence to endothelial cells via beta-2 integrin expression and synthesis of mediators of inflammation

PEDF is a trophic factor expressed by a multitude of retinal cells, an antagonist of VEGF. It decreases vascular permeability and plays an antioxidant role, protecting retinal cells from ROS. In the experimental setting, PEDF is decreased in aqueous and vitreous humor, early in preclinical stages of DR. The pathogenic mechanisms are supposed to be related with decreased insulin, as well as increased toxic mediators, such as glutamate. These early changes may induce mild changes in color vision, contrast sensitivity, visual field and electroretinogram oscillatory

• increased hematocrit and blood viscosity related to high liver synthesis of

• more rigid erythrocytes, with increased tendency to thrombosis

*2.2.2.1 Pigmented Epitelium Derived Factor (PEDF) decrease and retinal* 

*DOI: http://dx.doi.org/10.5772/intechopen.96548*

*2.2.1.4 Nitric oxide (NO) deficiency*

and secondary retinal ischemia.

ischemia:

*2.2.2 Changes in blood flow and platelet function*

• increased platelet adhesion and aggregation

fibrinogen and alfa2 globulins

*neurodegeneration*

### *Microvascular Complications of Diabetes Mellitus: Focus on Diabetic Retinopathy (DR)… DOI: http://dx.doi.org/10.5772/intechopen.96548*

Furthermore, experimental studies have proved a "hyperglycemic memory": in subjects with long periods of poor glycemic control, reversal of hyperglycemia fails to normalize increased oxidative activity in the retina [51]. Treatment with antioxidants and vitamin E alleviates endothelial dysfunction, but does not prevent the onset and progression of DR and other microvascular complications. Isolated experimental blockade of each of these pathways does not stop retinal microvascular damage, suggesting that the effects of hyperglycemia are manifested at the cellular and extracellular levels. Recently, experimental and clinical studies have demonstrated that inflammation biomarkers and pathways play a significant role in the aggravation of lesions and the evolution towards retinal neovascularization. A large array of cytokines and chemokines were found in increased concentrations in patients with DM, both in ocular samples and in serum: interleukin (Il)1beta, Il 2, 4, 6, 8, TNFalfa and (monocyte chemoattractant protein) MCP-1 [38, 42, 52–54]. Recent works have revealed that the TXNIP/NLRP3 Inflammasome activation pathways may contribute to pathologic neovascularization encountered in advanced stages of PDR [50, 54, 55].
